title: A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival.
abstract: With the advent of high-throughput sequencing technologies, much progress has been made in the identification of somatic structural rearrangements in cancer genomes. However, characterization of the complex alterations and their associated mechanisms remains inadequate. Here, we report a comprehensive analysis of whole-genome sequencing and DNA copy number data sets from The Cancer Genome Atlas to relate chromosomal alterations to imbalances in DNA dosage and describe the landscape of intragenic breakpoints in glioblastoma multiforme (GBM). Gene length, guanine-cytosine (GC) content, and local presence of a copy number alteration were closely associated with breakpoint susceptibility. A dense pattern of repeated focal amplifications involving the murine double minute 2 (MDM2)/cyclin-dependent kinase 4 (CDK4) oncogenes and associated with poor survival was identified in 5% of GBMs. Gene fusions and rearrangements were detected concomitant within the breakpoint-enriched region. At the gene level, we noted recurrent breakpoints in genes such as apoptosis regulator FAF1. Structural alterations of the FAF1 gene disrupted expression and led to protein depletion. Restoration of the FAF1 protein in glioma cell lines significantly increased the FAS-mediated apoptosis response. Our study uncovered a previously underappreciated genomic mechanism of gene deregulation that can confer growth advantages on tumor cells and may generate cancer-specific vulnerabilities in subsets of GBM.
authors.affiliation: Department of Bioinformatics and Computational Biology.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zheng
authors.forename: Jun
authors.initials: J
authors.lastname: Fu
authors.forename: Rahulsimham
authors.initials: R
authors.lastname: Vegesna
authors.forename: Yong
authors.initials: Y
authors.lastname: Mao
authors.forename: Lindsey E
authors.initials: LE
authors.lastname: Heathcock
authors.forename: Wandaliz
authors.initials: W
authors.lastname: Torres-Garcia
authors.forename: Ravesanker
authors.initials: R
authors.lastname: Ezhilarasan
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Wang
authors.forename: Aaron
authors.initials: A
authors.lastname: McKenna
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Brennan
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.forename: Dimpy
authors.initials: D
authors.lastname: Koul
authors.forename: Roel G W
authors.initials: RG
authors.lastname: Verhaak
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D019457:Chromosome Breakage; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics; D050939:Gene Fusion / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C097186:Faf1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4
keywords: Glioblastoma multiforme; The Cancer Genome Atlas; gene fusion; genomic instability; genomic rearrangement; intragenic breakpoint